Summary of work: Our main interests are to define the causes for age-associated deficits in bone remodeling activity and to develop novel treatment procedures for osteoporosis. In the past year, we have continued to focus on three areas. To test the hypothesis that the decline in the expression of extracellular matrix proteins in old bones may lead to impaired development and function of old bone cells, we examined the growth of osteoprogenitor cells in dishes coated with matrix proteins and the bone induction potential of these cells in subcutaneous implants. Although some matrix proteins can increase the number of osteoprogenitor colonies and, concurrently, reduce the number of colonies expressing alkaline phosphatase, a marker for preosteoblasts, these effects are the same, whether cells are derived from adult or old bones. Furthermore, we found that culturing of osteoprogenitor cells on matrix proteins has no apparent effect on bone induction potential regardless of the age of animals from which the cells are derived. Thus, we have concluded that the decline in the expression of matrix proteins in senescence may impair the growth of osteoprogenitor cells but not the bone induction potential of old progenitor cells. To gain insights into the stimulatory effect of IGF-I, infused locally, on femoral trabecular bone mass in old rats, we performed histomorphometric analysis to assess bone remodeling activity. Structural parameters (trabecular volume, number, and thickness) and indices associated with bone formation (osteoblast number, osteoblast surface, osteoid volume, and osteoid surface) are increased by IGF-I treatment. In contrast, indices associated with bone resorption (osteoclast number, osteoclast surface, and eroded surface) are reduced by IGF-I treatment. Kinetic indices (mineralizing surface, mineral apposition rate, and bone formation rate) are elevated in IGF-I treated femurs. We have concluded that locally infused IGF-I, at a low dose of 50 ng/d for 14 days, can increase trabecular bone mass by stimulating bone formation without any effect on bone resorption. To pursue the therapeutic application of minocycline in treatment of osteoporosis, we have initiated a phase II clinical trial using minocycline to treat postmenopausal osteoporosis. Currently, human subjects with bone mineral density (either in the spine or hip) at 2.5- 3.5 SD below the peak levels of young adults are being recruited for the study. The treatment period will be for one year with 200 mg of minocycline given daily. Bone mineral density will be determined before the treatment, at 6-month, 12-month during the treatment and 4-month after the conclusion of treatment. Serum and urine will be collected at 4-month intervals and markers of bone formation and resorption will be assayed during the treatment.